EP2176235B1 - A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) - Google Patents

A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) Download PDF

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Publication number
EP2176235B1
EP2176235B1 EP08773249A EP08773249A EP2176235B1 EP 2176235 B1 EP2176235 B1 EP 2176235B1 EP 08773249 A EP08773249 A EP 08773249A EP 08773249 A EP08773249 A EP 08773249A EP 2176235 B1 EP2176235 B1 EP 2176235B1
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EP
European Patent Office
Prior art keywords
telmisartan
methyl
benzimidazol
carboxylic acid
potassium
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EP08773249A
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German (de)
English (en)
French (fr)
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EP2176235A2 (en
Inventor
Jan Stach
Stanislav Radl
Josef Cinibulk
Ivo Strelec
Kamal Jarrah
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Zentiva KS
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Zentiva KS
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Priority to SI200830664T priority Critical patent/SI2176235T1/sl
Priority to PL08773249T priority patent/PL2176235T3/pl
Publication of EP2176235A2 publication Critical patent/EP2176235A2/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms

Definitions

  • the invention deals with an improved method of manufacturing 4'-[[4-methyl-6-(1-methyl-1 H -benzimidazol-2-yl)-2-propyl-1 H -benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) (I)
  • Telmisartan belongs to the group of angiotensin II antagonists, which are being therapeutically used as medicaments for the cardiovascular system, especially to control high blood pressure.
  • a dosage form of telmisartan was introduced in the market in 1998 by Boehringer Ingelheim under the protected name Micardis R .
  • This group contains important drugs like losartan (Cozaar R ), irbesartan (Avapro R ), or valsartan (Diovan R ).
  • telmisartan shows better efficiency even in the last hours of the administration interval.
  • Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim ( US 5 591 762 ) from telmisartan tert -butyl ester (II).
  • the hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N , N -dimethylformamide.
  • telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production.
  • telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.
  • Dr. Reddy WO 2006/044754
  • Dr. Reddy WO 2006/044754
  • telmisartan methylester hydrochloride which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C).
  • Teva (WO 2006/044648 ) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined.
  • the method comprises phase separations, which lead to low yields (69 % - 80 %) besides increased tediousness.
  • Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.
  • the object of the invention is an improved method of manufacturing 4'-[[4-methyl-6-(1-methyl-1 H -benzimidazol-2-yl)-2-propyl-1 H -benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) (I).
  • telmisartan 4'-[[4-methyl-6-(1-methyl-1 H -benzimidazol-2-yl)-2-propyl-1 H -benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) (I).
  • the essence consists in the surprising finding that filterability of the crystalline form A of telmisartan in alcohols depends on the content of water and hence its isolation from an anhydrous solvent is best.
  • filterability can be improved by the presence of potassium salts of carboxylic acids, which further significantly increases the yield of the process.
  • the table shows that in the industrial scale the amount of water and inorganic salts will be the key parameter of the process.
  • the amount of water has a principal impact on filterability of the product and an increased quantity of potassium salts of carboxylic acids reduces solubility of telmisartan and hence has a positive impact on the yield of the process. If the preparation of telmisartan starts from the corresponding methylester, it is also essential to get a product that does not contain inorganic substances. Therefore the inorganic salts used must display high solubility in the alcohols used.
  • the present invention provides a method of manufacturing the crystalline form A of telmisartan, in which a carboxylic acid of the general formula R 1 COOH, wherein R 1 is the hydrogen atom or a C 1 -C 4 alkyl, is added to a solution of the potassium salt of telmisartan in an alcohol of the formula R 2 OH with the water content lower than 2%, wherein R 2 is ethyl or methyl.
  • the potassium salt of telmisartan is obtained by hydrolysis of a telmisartan alkyl ester of the general formula (VIII)
  • telmisartan It is convenient if the potassium salt of telmisartan is obtained by neutralization of telmisartan with potassium hydroxide.
  • the content of the obtained potassium salt of the carboxylic acid R 1 COOH, expressed as the salt/telmisartan weight ratio, is 20% - 150% during crystallization.
  • the content of water in the system is lower than 1%.
  • the invention provides a method of manufacturing the crystalline form A of telmisartan, characterized in that a telmisartan ester (VIII) is heated up in methanol with the water content lower than 1% by weight together with potassium hydroxide to the boiling temperature for 12 to 48 hours, formic or acetic acid is added to the solution and after cooling the crystalline product of form A is separated.
  • VIII telmisartan ester
  • telmisartan of form A is crystallized at a temperature of -10 to +10 °C.
  • telmisartan potassium hydroxide and formic or acetic acid is selected so as to produce the resulting weight ratio of the potassium salt of the selected organic acid to the resulting telmisartan of 1 : 2 to 6 : 5.
  • telmisartan methylester hydrolysis of telmisartan methylester can be most suitably carried out with potassium hydroxide in anhydrous methanol; after the reaction is complete, the crystalline form A of telmisartan is obtained by addition of acetic or formic acids.
  • the product contains a considerable quantity of potassium acetate or formate, it has been found out that the reaction provides the product with a low content of potassium acetate or formate expressed by a low content of sulfate ash. Such mode of carrying out the reaction then complies with the requirements for a synthesis carried out in an industrial scale.
  • Telmisartan methylester (VI) 40 g was refluxed in methanol (440 ml) with potassium hydroxide (14.9 g) for 24 hours. To the boiling solution, methanol (240 ml) and then acetic acid (45.5 g) were added. While boiling, the mixture was stirred for another 1 hour, after cooling to 4°C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 35.18 g (90 %) of the product were obtained.
  • Telmisartan methylester (VI) (20 g) was refluxed in methanol (300 ml) with potassium hydroxide (7 g) for 24 h. After addition of formic acid (17 g) and after cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 18.7 g (96 %) of the product were obtained.
  • Telmisartan methylester (VI) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained.
  • Telmisartan methylester 40 g was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP08773249A 2007-07-09 2008-07-08 A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) Active EP2176235B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200830664T SI2176235T1 (sl) 2007-07-09 2008-07-08 Postopek za proizvodnjo 4'-((4-metil-6-(1-metil-1h-benzimidazol-2-il)-2-propil-1h-benzimidazol- 1il)metil)bifenil-2-karboksilne kisline (telmisartan)
PL08773249T PL2176235T3 (pl) 2007-07-09 2008-07-08 Sposób wytwarzania kwasu 4’-[[4-metylo-6-(1-metylo-1H-benzimidazol-2-ilo)-2-propylo-1H-benzimidazol-1-ilo]metylo]bifenylo-2-karboksylowego (telmisartanu)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20070457A CZ302272B6 (cs) 2007-07-09 2007-07-09 Zpusob výroby 4´-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-yl]methyl]biphenyl-2-karboxylové kyseliny (telmisartanu)
PCT/CZ2008/000080 WO2009006860A2 (en) 2007-07-09 2008-07-08 A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Publications (2)

Publication Number Publication Date
EP2176235A2 EP2176235A2 (en) 2010-04-21
EP2176235B1 true EP2176235B1 (en) 2012-04-18

Family

ID=40229130

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08773249A Active EP2176235B1 (en) 2007-07-09 2008-07-08 A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Country Status (13)

Country Link
US (1) US20100222402A1 (xx)
EP (1) EP2176235B1 (xx)
AT (1) ATE554074T1 (xx)
CZ (1) CZ302272B6 (xx)
EA (1) EA015790B1 (xx)
ES (1) ES2386678T3 (xx)
HR (1) HRP20120501T1 (xx)
PL (1) PL2176235T3 (xx)
PT (1) PT2176235E (xx)
RS (1) RS52426B (xx)
SI (1) SI2176235T1 (xx)
UA (1) UA99140C2 (xx)
WO (1) WO2009006860A2 (xx)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010004385A1 (en) * 2008-06-17 2010-01-14 Aurobindo Pharma Limited Process for the preparation of pure 4'-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid
WO2010018441A2 (en) * 2008-08-11 2010-02-18 Cadila Pharmaceuticals Ltd. An improved process for the preparation of substantially pure telmisartan
EA025946B1 (ru) 2010-10-27 2017-02-28 Крка, Товарна Здравил, Д. Д., Ново Место Многослойная фармацевтическая композиция, содержащая телмисартан и амлодипин
ITMI20102416A1 (it) * 2010-12-27 2012-06-28 Chemelectiva S R L Intermedio per la preparazione di un principio attivo e processo per la sua preparazione
JP6147546B2 (ja) * 2013-04-10 2017-06-14 株式会社トクヤマ 酢酸が低減されたテルミサルタンａ型結晶の製造方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591762A (en) * 1991-02-06 1997-01-07 Dr. Karl Thomae Gmbh Benzimidazoles useful as angiotensin-11 antagonists
US6358986B1 (en) * 1999-01-19 2002-03-19 Boehringer Ingelheim Pharma Kg Polymorphs of telmisartan
DE10314702A1 (de) 2003-03-31 2004-10-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung von Telmisartan
GB2414019A (en) 2004-05-11 2005-11-16 Cipla Ltd One-step preparation of telmisartan by condensation and hydrolysis
CA2581723A1 (en) * 2004-10-15 2006-04-27 Teva Pharmaceutical Industries Ltd. Process for preparing telmisartan
WO2006044754A2 (en) * 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Process for preparing telmisartan
US20060211866A1 (en) * 2005-03-21 2006-09-21 Glenmark Pharmaceuticals Limited Process for the preparation of angiotensin receptor blockers and intermediates thereof

Also Published As

Publication number Publication date
CZ2007457A3 (cs) 2009-02-11
EA015790B1 (ru) 2011-12-30
EP2176235A2 (en) 2010-04-21
WO2009006860A3 (en) 2009-04-16
US20100222402A1 (en) 2010-09-02
SI2176235T1 (sl) 2012-10-30
PT2176235E (pt) 2012-07-02
EA201000065A1 (ru) 2010-06-30
PL2176235T3 (pl) 2012-09-28
CZ302272B6 (cs) 2011-01-19
ES2386678T3 (es) 2012-08-24
WO2009006860A2 (en) 2009-01-15
UA99140C2 (ru) 2012-07-25
ATE554074T1 (de) 2012-05-15
HRP20120501T1 (hr) 2012-10-31
RS52426B (en) 2013-02-28

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